RAD51C c.905-19T>C, p.?

Reasoning

PM2_Supporting is met under the generic population-frequency fallback. Although present in gnomAD, the most conservative available filtering allele frequency is 0.008818% (v2.1) and 0.005694% (v4.1), each below 0.1%; this is sufficiently rare for PM2_Supporting. No extractable RAD51C-specific PM2 threshold was present in the retrieved VCEP material.

Rule

Generic population-frequency fallback: PM2_Supporting may be applied when the maximum credible population frequency is <0.1% and no RAD51C-specific threshold is available.

Evidence considered

• gnomAD v2.1: 17/251,224 alleles (AF 0.006767%), grpmax FAF 0.008818%, with no homozygotes; the highest broad-population AF is 0.014085% in non-Finnish Europeans (16/113,594 alleles).
• gnomAD v4.1: 90/1,598,884 alleles (AF 0.005629%), grpmax FAF 0.005694%, with no homozygotes; the highest broad-population AF is 0.011292% in Remaining individuals (7/61,992 alleles).
• The variant is absent from gnomAD-Canada v1.0.
• The gnomAD v2.1 filtering allele frequency is used conservatively because it is higher than the v4.1 filtering allele frequency.

Sources

Reasoning

Applying the generic ACMG/AMP splice-path threshold (no RAD51C VCEP-specific PP3/BP4 spreadsheet available) to this deep intronic variant: SpliceAI max delta score = 0.016, well below the BP4 supporting threshold of <0.1, indicating no predicted splice impact. BP4 is met at supporting strength. REVEL and BayesDel are not applicable here (variant is not missense) and BayesDel is not used under this pipeline's calibration policy regardless of variant type since no verified published threshold/PMID is available.

Rule

generic_acmg_pp3_bp4_splice_path

Evidence considered

• SpliceAI max delta score = 0.016 (DS_AG=0.0, DS_AL=0.013, DS_DG=0.0, DS_DL=0.016), well below the 0.1 BP4 supporting threshold for intronic variants (source: spliceai).
• Generic ACMG/AMP in-silico calibration (output/generic_acmg_classification_rules.md, source basis PMID:25741868, SVI-recommended SpliceAI thresholds as also reflected in VCEP CSPEC specifications such as ATM's per Walker et al. 2023): SpliceAI max delta <0.1 -> BP4 supporting for intronic/synonymous/non-canonical splice-position variants.
• BayesDel score for this variant was retrieved (score present in prefetch data) but is not used for PP3/BP4 per this pipeline's policy: no verified published calibration threshold/PMID is available for BayesDel, so it is treated as not_available regardless of the raw score.
• REVEL is not applicable because this variant is intronic, not missense; REVEL score field returned null/not found in this case's evidence anyway.

Sources

Reasoning

NM_058216.3:c.905-19T>C is a deep intronic variant (not a missense substitution and not a canonical +/-1,2 splice consensus change), so per the generic ACMG/AMP in-silico calibration (no RAD51C VCEP-specific PP3/BP4 lookup spreadsheet was retrieved for this gene; vcep_materials and vcep_db/RAD51C contain no gene-specific PP3/BP4 rule payload), only the SpliceAI splice-path threshold applies. SpliceAI max delta score is 0.016, well below the PP3 supporting threshold of >0.2, so PP3 is not met.

Rule

generic_acmg_pp3_bp4_splice_path

Evidence considered

• SpliceAI predicts no significant splice impact for this variant: DS_AG=0.0, DS_AL=0.013, DS_DG=0.0, DS_DL=0.016, max delta score = 0.016 (source: spliceai).
• Generic ACMG/AMP in-silico calibration (output/generic_acmg_classification_rules.md, cited as generic_acmg_combination_rules, source basis PMID:25741868) specifies for intronic/synonymous/non-canonical-splice-position variants: SpliceAI max delta >0.2 -> PP3, <0.1 -> BP4, [0.1,0.2] gray zone; missense-path REVEL rule does not apply to this intronic variant.
• No RAD51C VCEP/CSPEC gene-specific PP3/BP4 lookup spreadsheet was found (vcep_materials.summaries empty, vcep_db/RAD51C/criteria.json empty, rule_payload empty in final_classification_framework), so the generic fallback governs.

Sources

Reasoning

No exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is present. PP5 is not supported.

Rule

PP5 requires an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion; ordinary laboratory submissions and aggregate ClinVar labels do not qualify.

Evidence considered

• ClinVar variation 492395 is an exact transcript-level match, but its six submissions are Benign or Likely benign laboratory submissions and the submission audit reports zero expert-panel submissions.

Sources

Reasoning

BA1 is not met. The highest available filtering allele frequency is 0.008818% in gnomAD v2.1 and 0.005694% in gnomAD v4.1, far below the generic BA1 stand-alone benign threshold of >1%. No extractable RAD51C-specific BA1 threshold was present in the retrieved VCEP material.

Rule

Generic population-frequency fallback: BA1 requires allele frequency >1% in a relevant population dataset.

Evidence considered

• The retrieved RAD51C VCEP material identifies the RAD51C disease contexts but contains no criterion-level rule payload or population-frequency thresholds; generic population thresholds were therefore used.
• gnomAD v2.1 reports 17/251,224 alleles (AF 0.006767%; grpmax FAF 0.008818%) and no homozygotes.
• gnomAD v4.1 reports 90/1,598,884 alleles (AF 0.005629%; grpmax FAF 0.005694%) and no homozygotes.

Sources

Reasoning

BS1 is not met. The maximum observed population frequency is 0.038364% in the small NFE_SWE subset of gnomAD v2.1 (10/26,066 alleles), while the v2.1 grpmax FAF is 0.008818% and v4.1 grpmax FAF is 0.005694%; all are below the generic BS1 threshold of >0.3%. No extractable RAD51C-specific BS1 threshold was present in the retrieved VCEP material.

Rule

Generic population-frequency fallback: BS1 requires allele frequency >0.3%, exceeding that expected for a pathogenic RAD51C allele.

Evidence considered

• The v2.1 highest raw subpopulation AF (NFE_SWE, 10/26,066 = 0.038364%) is based on a limited allele count and remains below 0.3%; the cohort-wide v2.1 grpmax FAF is 0.008818%.
• gnomAD v4.1 has a cohort-wide grpmax FAF of 0.005694%; its highest reported broad subpopulation AF is 0.011292% in Remaining individuals (7/61,992 alleles).
• No homozygotes were reported in either gnomAD release.

Sources

Reasoning

BS2 is not met. gnomAD v2.1 and v4.1 each report zero homozygotes. Moreover, the available population records do not establish phenotype, age, or disease-free status for carriers; therefore, healthy-adult observations required for BS2 are absent.

Rule

Generic ACMG/AMP BS2: observed in a healthy adult individual for a disorder expected to be fully penetrant at an early age; neither the required healthy-adult observation nor homozygote observation is available here.

Evidence considered

• gnomAD v2.1 reports zero homozygotes among 17 alternate alleles, and gnomAD v4.1 reports zero homozygotes among 90 alternate alleles.
• Population-database carrier counts alone do not document that an individual is unaffected at an age informative for RAD51C-associated hereditary cancer predisposition.

Still missing

• No genotype-confirmed healthy-adult or unaffected-carrier dataset with phenotype and age information was provided.

Sources

Reasoning

No exact-variant ClinVar expert-panel Benign or Likely benign classification is present. BP6 is not supported.

Rule

BP6 requires an exact-variant ClinVar expert-panel Benign or Likely benign assertion; ordinary laboratory submissions and aggregate ClinVar labels do not qualify.

Evidence considered

• ClinVar variation 492395 is an exact transcript-level match, but all six submissions are single-submitter laboratory assertions and the submission audit reports zero expert-panel submissions.

Sources

Reasoning

Not assessed: no proband-level parental testing, parentage confirmation, phenotype information, or de novo observation is present in the consolidated case-evidence bundle.

Rule

Generic ACMG/AMP PS2: de novo occurrence in a patient with the disease and no family history, with maternity and paternity confirmed.

Evidence considered

• The retrieved RAD51C CSPEC record has an empty criteria payload; it supplies no usable gene-specific PS2 rule, so the generic ACMG/AMP definition was used.
• The consolidated case-evidence bundle contains no proband observation, parental genotypes, parentage testing, phenotype, or de novo report for this variant.

Still missing

• Obtain the proband genotype and phenotype.
• Obtain testing of both biological parents for NM_058216.3:c.905-19T>C, including confirmation of parentage and assessment for parental mosaicism if absent in blood.
• Establish whether the proband phenotype is specific and consistent with a RAD51C-associated disorder before assigning de novo evidence.

Sources

Reasoning

No functional assay data (splicing minigene/RT-PCR, HDR/complementation assay, or other validated functional study) for NM_058216.3:c.905-19T>C is present anywhere in the case evidence bundle (evidence.json, literature_pass.json, fulltext_map.json). The ClinGen HBOP VCEP RAD51C specification (v1.0) supports PS3/BS3 only via validated splicing or homology-directed repair (HDR) assays with appropriate controls; none were located for this variant. SpliceAI is a computational predictor, not a functional assay, and does not satisfy PS3/BS3.

Still missing

• No published or cited RNA/splicing functional assay (RT-PCR, minigene) for this variant
• No published HDR/complementation functional assay for this variant
• No functional data located in ClinVar submissions or cited literature (PMID:25741868, PMID:25085752, PMID:25394175, PMID:20301575, PMID:28492532) specific to this variant

Reasoning

No case-control or other statistically valid enrichment evidence for NM_058216.3:c.905-19T>C was retrieved. ClinVar submitter classifications are not case-control data and were not used to infer PS4.

Rule

Generic ACMG/AMP PS4: prevalence in affected individuals must be significantly increased compared with controls; no usable enrichment dataset was retrieved.

Evidence considered

• The retrieved RAD51C CSPEC identifies hereditary breast/ovarian cancer and Fanconi anemia disease contexts but contains no extracted PS4 rule payload or case-control threshold.
• The exact ClinVar record contains laboratory submissions only; it supplies no case/control counts, odds ratio, confidence interval, or enrichment statistic for this variant.

Still missing

• A variant-specific, phenotype-defined case-control dataset or adequately powered enrichment analysis with control counts and statistical results is required.

Sources

Reasoning

PM3 cannot be evaluated: the case bundle contains no affected individual with this variant, no second RAD51C variant classified as pathogenic or likely pathogenic, and no phase evidence. Although the retrieved RAD51C specification identifies autosomal-recessive Fanconi anemia as a RAD51C disease context, no phenotype or biallelic observation relevant to that disorder is provided.

Rule

No explicit RAD51C PM3 specification was retrieved. Under generic ACMG/AMP use, PM3 requires observation with a pathogenic variant in trans in an affected individual with a recessive disorder; this evidence is absent.

Evidence considered

• The retrieved RAD51C CSPEC framework lists autosomal-dominant familial ovarian cancer and hereditary breast carcinoma, and autosomal-recessive Fanconi anemia. The bundle supplies no proband-level genotype, phenotype, companion-variant, or phase data for the submitted variant.

Still missing

• An affected proband with a phenotype compatible with autosomal-recessive RAD51C-related Fanconi anemia.
• A confirmed pathogenic/likely pathogenic RAD51C variant in the same individual and validated trans phase (or adequate phase inference).
• The companion variant's classification and the observation-level evidence needed to assign PM3 strength.

Sources

Reasoning

Not assessed: no reported de novo occurrence or parental testing is available. PM6 cannot be assigned merely because parental data are absent.

Rule

Generic ACMG/AMP PM6: assumed de novo occurrence in a patient with the disease and no family history when maternity and paternity are not confirmed.

Evidence considered

• The retrieved RAD51C CSPEC record has an empty criteria payload; it supplies no usable gene-specific PM6 rule, so the generic ACMG/AMP definition was used.
• The consolidated case-evidence bundle contains no proband observation, parental genotypes, parentage testing, phenotype, or de novo report for this variant.

Still missing

• Obtain the proband genotype and phenotype.
• Obtain testing of both biological parents for NM_058216.3:c.905-19T>C.
• If the variant is absent from both parents, document whether parentage has been confirmed and evaluate phenotype consistency.

Sources

Reasoning

Not assessed: no informative relatives, disease statuses, genotypes, pedigrees, or count of independent segregations are reported for this variant.

Rule

Generic ACMG/AMP PP1: co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease; strength may increase with additional segregation data.

Evidence considered

• The retrieved RAD51C CSPEC record has an empty criteria payload; it supplies no usable gene-specific PP1 rule, so the generic ACMG/AMP definition was used.
• The consolidated case-evidence bundle contains no family-level genotypes, phenotypes, pedigree data, or meiosis count for this variant.

Still missing

• Obtain a pedigree with affected and unaffected relatives, their relevant diagnoses and ages.
• Genotype informative relatives for NM_058216.3:c.905-19T>C and document the number of informative meioses.
• Assess whether affected-relative phenotypes are consistent with the RAD51C-associated condition under evaluation.

Sources

Reasoning

No phenotype, personal/family cancer history, or phenotype-specificity analysis for the tested individual was provided. Therefore, phenotype specificity for a RAD51C-associated condition cannot be assessed.

Rule

Generic ACMG/AMP PP4: the patient's phenotype or family history must be highly specific for a disease with a single genetic etiology; the necessary patient data are absent.

Evidence considered

• The retrieved RAD51C CSPEC lists familial ovarian cancer, hereditary breast carcinoma, and Fanconi anemia as disease contexts, but no patient phenotype accompanies this variant record.

Still missing

• Phenotypic and family-history data for the tested individual, including the relevant RAD51C-associated disease context, are required.

Sources

Reasoning

No functional assay data (splicing minigene/RT-PCR, HDR/complementation assay, or other validated functional study) for NM_058216.3:c.905-19T>C is present anywhere in the case evidence bundle. The ClinGen HBOP VCEP RAD51C specification supports BS3 only via validated functional assays with normal-range results and appropriate controls; none were located. SpliceAI's low predicted delta score (max 0.016) is a computational prediction, not functional assay evidence, so it cannot be used to meet BS3.

Still missing

• No functional assay (splicing or HDR) with normal/wild-type-like results reported for this variant
• No cited literature source provides direct functional characterization of this specific variant

Reasoning

Not assessed: no informative affected non-carrier or unaffected carrier observations, family phenotypes, or segregation data are reported for this variant.

Rule

Generic ACMG/AMP BS4: lack of segregation in affected members of a family.

Evidence considered

• The retrieved RAD51C CSPEC record has an empty criteria payload; it supplies no usable gene-specific BS4 rule, so the generic ACMG/AMP definition was used.
• The consolidated case-evidence bundle contains no family-level genotypes, phenotypes, or reported non-segregation observations for this variant.

Still missing

• Obtain a pedigree and genotype-phenotype data for informative relatives.
• Document any unequivocal non-segregation, including affected non-carriers or unaffected carriers, while accounting for age-related penetrance and phenocopies.

Sources

Reasoning

BP2 cannot be evaluated because the bundle provides no individual-level co-occurrence data for this variant with a RAD51C pathogenic/likely pathogenic variant, no cis/trans phase, and no phenotype or penetrance context. Aggregate ClinVar classifications are not co-occurrence evidence and were not used to infer BP2.

Rule

No explicit RAD51C BP2 specification was retrieved. Under generic ACMG/AMP use, BP2 requires a documented co-occurrence with a pathogenic/likely pathogenic variant in cis or in trans in an appropriate dominant-disease context; this evidence is absent.

Evidence considered

• The retrieved RAD51C CSPEC framework identifies both autosomal-dominant cancer-predisposition and autosomal-recessive Fanconi-anemia disease contexts. No co-occurrence or phase observation for NM_058216.3:c.905-19T>C is present in the case bundle.

Still missing

• A documented co-occurring pathogenic/likely pathogenic RAD51C variant in the same individual.
• Validated cis or trans phase for the two variants.
• Phenotype, disease context, and penetrance information sufficient to determine whether the co-occurrence is incompatible with the relevant RAD51C disease mechanism.

Sources

Reasoning

No evidence was retrieved that the individual's phenotype is explained by an alternative molecular diagnosis, and no phenotype was supplied for such an assessment.

Rule

Generic ACMG/AMP BP5: a variant may support benignity when a different molecular diagnosis fully explains the patient's phenotype; this evidence was not provided.

Evidence considered

• The consolidated case evidence contains no patient phenotype and no alternative molecular diagnosis or co-occurrence assessment.

Still missing

• A phenotype-correlated alternative molecular diagnosis demonstrating that it fully explains the observed presentation is required.